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  • Stabile L Buonanno G Ficco G Scungio

    2019-10-18

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    Contents lists available at ScienceDirect
    Journal of Inorganic Biochemistry
    journal homepage: www.elsevier.com/locate/jinorgbio
    A novel binuclear hydrazone-based Cd(II) complex is a strong pro-apoptotic T inducer with significant activity against 2D and 3D pancreatic cancer stem cells
    Snežana Bjelogrlića,b, Tamara R. Todorovićc, Ilija Cvijetićd, Marko V. Rodiće, Miroslava Vujčićf, Sanja Markovićc, Jovana Araškovc, Barbara Janovićf, Fathi Emhemmedb, Christian D. Mullerb, Nenad R. Filipovićg, a National Cancer Research Center of Serbia, Pasterova 14, Belgrade, Serbia b Institut Pluridisciplinaire Hubert Curien, UMR 7178 CNRS Université de Strasbourg, 67401 Illkirch, France c Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, Belgrade, Serbia d Innovation Center of the Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, Belgrade, Serbia e Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, Novi Sad, Serbia f Institute of Chemistry, Technology and Metallurgy, University of Belgrade, Njegoševa 12, Belgrade, Serbia g Faculty of Agriculture, University of Belgrade, Nemanjina 6, Belgrade, Serbia
    Keywords:
    Cd(II) complex
    Hydrazones
    Apoptosis
    Cancer stem cells
    DNA interactions
    HSA interactions 
    A novel binuclear Cd complex (1) with hydrazone-based ligand was prepared and characterized by spectroscopy and single crystal X-ray diffraction techniques. Complex 1 reveals a strong pro-apoptotic activity in both human, mammary adenocarcinoma cells (MCF-7) and pancreatic AsPC-1 cancer stem cells (CSCs). While apoptosis undergoes mostly caspase-independent, 1 stimulates the activation of intrinsic pathway with noteworthy down regulation of caspase-8 activity in respect to non-treated controls. Distribution of cells over mitotic division indicates that 1 caused DNA damage in both cell lines, which is confirmed in DNA interaction studies. Compared to 1, cisplatin (CDDP) does not achieve cell death in 2D cultured AsPC-1 cells, while induces different pattern of cell cycle changes and caspase activation in 2D cultured MCF-7 cells, implying that these two compounds do not share similar mechanism of action. Additionally, 1 acts as a powerful inducer of mitochondrial superoxide production with dissipated trans-membrane potential in the majority of the treated cells already after 6 h of incubation. On 3D tumors, 1 displays a superior activity against CSC model, and at 100 μM induces disin-tegration of spheroids within 2 days of incubation. Fluorescence spectroscopy, along with molecular docking show that compound 1 binds to the minor groove of DNA. Compound 1 binds to the human serum albumin (HSA) showing that the HSA can effectively transport and store 1 in the human body. Thus, our current study strongly supports further investigations on antitumor activity of 1 as a drug candidate for the treatment of highly resistant pancreatic cancer.